Scott André Oakes, MD

Research and Clinical Interests

ER Stress, Cell Suicide and Disease

All multicellular organisms have evolved mechanisms to silence or eliminate rogue cells that threaten the survival of the majority. As such, human cells are genetically programmed to actively commit “suicide” through a process called apoptosis when they become harmful, superfluous or irreversibly damaged. The final executioners in the apoptotic pathway are a family of proteins called caspases that ultimately digest the cell from the inside out. While great strides have been made in identifying the core apoptotic machinery that dismantles the cell, we still know relatively little about how the process begins. In particular, we are largely ignorant of how cells sense internal damage (say in response to chemotherapy), determine if the damage is lethal, and then relay this information to the apoptotic machinery. Various physiological events (e.g., secretory cell differentiation) and pathological conditions (e.g., hypoxia, nutrient deprivation) can overwhelm the protein folding capacity of the endoplasmic reticulum (ER). Initially, the stress placed on the ER by an abundance of misfolded protein activates an evolutionarily conserved signal transduction pathway called the unfolded protein response (UPR) that initially expands the ER network and upregulates protein folding capacity in order to restore homeostasis. However, if the ER damage is extensive or prolonged, cells initiate apoptosis. Mounting evidence suggests that apoptosis triggered by excessive stress on the protein folding capacity of the ER contributes to pathological cell loss in many common human degenerative diseases, including Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis, type 2 diabetes, and liver cirrhosis. We are currently designing pharmacological interventions to precisely control and tune these signaling switches with small molecules to influence cell survival and prevent these diseases.